Hypoxic pulmonary vasoconstriction in conscious sheep: role of mast cell degranulation.
We used pharmacologic and histologic techniques to investigate the role of mast cells in the mediation of hypoxic pulmonary vasoconstriction in conscious sheep. Breathing a hypoxic gas mixture (13%, 02, 87% nitrogen) caused hypoxic pulmonary vasoconstriction (HPV) with increases in mean pulmonary artery pressure and pulmonary vascular resistance by 97 and 90%, respectively. Intravenous pretreatment with the mast cell membrane stabilizing agent cromolyn sodium (3 mg/kg/min) completely blocked HPV, whereas the H1-histamine receptor antagonist chlorpheniramine, alone or in combination with the H2-receptor antagonist metiamide and the prostaglandin synthetase inhibitor indomethacin, failed to prevent HPV. Cromolyn sodium failed to modify the pulmonary pressor response to infusions of norepinephrine (alpha-agonist), tyramine (catecholamine-releasing agent), and histamine, indicating the specificity of cromolyn sodium action on the mast cells. Electromicroscopic studies of pulmonary perivascular mast cells showed that a 90-min exposure to the hypoxic gas mixture reduced the total number of granules per mast cell to 75% of control. This was blocked by cromolyn sodium pretreatment. We conclude that in conscious sheep], HP[V is initiated by the liberation of a mast cell product (other than histamine) that either directly or indirectly causes pulmonary vasoconstriction.
D000818:Animals; D002744:Chlorpheniramine / Q000494:pharmacology; D004205:Cromolyn Sodium / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000502:physiology*; D005260:Female; D006439:Hemodynamics; D000860:Hypoxia / Q000503:physiopathology*; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000098:blood supply*; D008407:Mast Cells / Q000502:physiology* / Q000648:ultrastructure; D008785:Metiamide / Q000494:pharmacology; D012756:Sheep; D014661:Vasoconstriction / Q000187:drug effects
D008785:Metiamide; D002744:Chlorpheniramine; D004205:Cromolyn Sodium; D007213:Indomethacin